Abstract
Childhood acute lymphoblastic leukemia (ALL) can often be traced to a pre-leukemic clone carrying a prenatal genetic lesion. Postnatally acquired mutations then drive clonal evolution toward overt leukemia. The enzymes RAG1-RAG2 and AID, which diversify immunoglobulin-encoding genes, are strictly segregated in developing cells during B lymphopoiesis and peripheral mature B cells, respectively. Here we identified small pre-BII cells as a natural subset with increased genetic vulnerability owing to concurrent activation of these enzymes. Consistent with epidemiological findings on childhood ALL etiology, susceptibility to genetic lesions during B lymphopoiesis at the transition from the large pre-BII cell stage to the small pre-BII cell stage was exacerbated by abnormal cytokine signaling and repetitive inflammatory stimuli. We demonstrated that AID and RAG1-RAG2 drove leukemic clonal evolution with repeated exposure to inflammatory stimuli, paralleling chronic infections in childhood.
MeSH terms
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Adolescent
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Animals
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Antibody Diversity / genetics
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Antibody Diversity / immunology
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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Child
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Child, Preschool
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Clonal Evolution / genetics
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Clonal Evolution / immunology*
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Cytidine Deaminase / genetics
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Cytidine Deaminase / immunology
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Cytidine Deaminase / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology
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DNA-Binding Proteins / metabolism
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Female
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Flow Cytometry
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Homeodomain Proteins / genetics
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Homeodomain Proteins / immunology
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Homeodomain Proteins / metabolism
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Humans
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Immunoblotting
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Infant
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Male
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Mice, Transgenic
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Microscopy, Fluorescence
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor Cells, B-Lymphoid / immunology*
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Precursor Cells, B-Lymphoid / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Cells, Cultured
Substances
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DNA-Binding Proteins
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Homeodomain Proteins
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V(D)J recombination activating protein 2
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RAG-1 protein
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AICDA (activation-induced cytidine deaminase)
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Cytidine Deaminase